Apoptosis is a process involving programmed cell death or “cellular suicide” and under physiological conditions it occurs after cell surface death receptors are occupied or activated by various genotoxic agents. This process leads to mitochondrial release of cytochrome C, which in turn activates the caspase enzymes that promote apoptosis.
Since apoptosis was first described in 1972 by Kerr et al. (1), much knowledge has been accumulated about this important cellular process. Although a comprehensive understanding of apoptosis at the molecular level and cellular level is yet to be achieved, the knowledge accumulated thus far has led to the realization that because the process is genetically programmed, it may be susceptible to the effects of mutation and, therefore, may be involved in the pathogenesis of a variety of human diseases such as viral infections, autoimmune diseases and cancer (2, 3). Based on this realization, it has been widely recognized that any therapeutic strategy aimed at specifically triggering apoptosis in diseased cells that suffer from disregulation of apoptosis (e.g. cancer) may deliver potentially promising therapies.
In a recent article, Ferreira et al. (4) have reviewed current strategies for exploiting the therapeutic potentials of apoptosis. To summarize the review, existing strategies for apoptosis-based therapies can be grouped into two types: the proapoptotic approaches and the apoptosis-permissive approaches. Table 1 shows a list of exemplary approaches in each category.
The proapoptic approaches are strategies that aim to directly induce apoptosis. They try to achieve apoptosis through exploitation of existing cellular players and pathways such as death receptors and caspases, or the introduction of exogenous proapoptotic molecules such as Apoptin. Proapoptotic strategies can involve: (a) direct introduction of proapoptotic players; (b) modulation of antiapoptotic molecules; or (c) restoration of tumor suppressor gene function. However, proapotic strategies are not based on structural differences between normal and cancer cells. Therefore, achieving tumor cell specificity, while minimizing toxicity, poses a major challenge in the development of this type of approaches For example, experimental therapies targeting death receptors such as TNF and Fas have resulted in ischemic and hemorrhagic lesions in several tissues.
The apoptosis-permissive approaches, on the other hand, is based on the premises that by blocking some of the intricate signaling pathways mediating survival messages that in normal conditions contribute to keep the cellular homeostasis, apoptosis may be triggered. This type of strategies do not have the non-specific toxicity problems of the proapoptotic approaches, however, successful development of this type of strategies is highly dependent on a detailed knowledge of the mechanisms by which apoptosis is facilitated. Thus far, our understanding and knowledge of such mechanisms leading to the secondary effect of apoptosis are still incomplete.
Therefore, there still exists a need for new strategies to selectively induce apoptosis in diseased cells, and new tools and methods for implementing the same.